The present invention relates generally to methods of treatment of gastrointestinal or systemic diseases. In particular, the present invention relates to methods of treatment or prevention of gastrointestinal or systemic diseases by administration of adenosine without causing adverse reactions.
Adenosine has promise for the treatment or prevention of several bowel diseases. It is well known that adenosine has the ability to dilate the splanchnic circulation (see e.g., Proctor, K. G., Circulation Res. 59:474 (1986); Proctor, K. G., Circulation Res. 61:187 (1987); Jackson, E. K., Am. J. Physiol. 253:H909 (1987); Kuan, C. J., et al., Am. J. Physiol. 255:H386 (1988); and Holycross, B. J., et al., J. Pharmacol. Exp. Ther. 250:433 (1989) (hereinafter xe2x80x9cHolycross, et al. (1989)xe2x80x9d), the disclosures of which are incorporated herein by reference) inhibit platelet activation (see e.g., Dawicki, D. D., et al., Thromb. Res. 43:161 (1986); Paul, S., et al., J. Pharmacol. Exp. Ther. 267:838 (1993); and Cristalli, G., et al., Naunyn-Schmiedebergs Archives of Pharmacology 349:644 (1994), the disclosures of which are incorporated herein by reference) ; and attenuate neutrophil function (see e.g., Cronstein, B. N., J. App. Phsiol. 76:5 (1994) (hereinafter, xe2x80x9cCronstein (1994)xe2x80x9d); Revan, S., et al., J. Biol. Chem. 271:17114 (1996); and Jordan, J. E., J. Pharmacol. Exp. Ther. 280:301 (1997), the disclosures of which are incorporated herein by reference). It has been further demonstrated that locally applied adenosine protects intestinal segments from ischemia/repercussion injury. See, Kaminski, P. M., et al., Circulation Res. 65:426 (1989) and Kaminski, P. M., et al., Circulation Res. 71:720 (1992), the disclosures of which are incorporated herein by reference. Adenosine may also be useful in the treatment of inflammatory diseases of the bowel such as Crohn""s disease and ulcerative colitis because adenosine inhibits inflammatory cell function (Cronstein (1994)). It is also known that adenosine attenuates the production of inflammatory cytokines such as TNFxcex1 (Wagner, D. R., et al., Circulation 97:521 (1998); and Cain, B. S., et al., J. Surg. Res. 76:117 (1998), the disclosures of which are incorporated herein by reference). Moreover, adenosine inhibits fibroblast proliferation (Dubey, R. K., et al., Circulation 96:2656 (1997), the disclosure of which is incorporated herein by reference) extracellular matrix production by fibroblasts (Dubey, R. K., et al., Hypertension 31:943 (1998), the disclosure of which is incorporated herein by reference), and inflammation (Cronstein (1994)), all processes which are involved in the formation of intestinal adhesions (Klein, E. S., et al., J. Surg. Res. 61:473 (1996), the disclosure of which is incorporated herein by reference). The formation of intestinal adhesions is a major source of surgical morbidity (Thompson, J., Digest. Surg. 15:153 (1998), the disclosure of which is incorporated herein by reference).
The adverse effects of adenosine, however, limit the usefulness of this agent as a systemically (intravenously or intra-arterially) administered drug. When so administered, adenosine can cause heart block, asystole, arrhythmias, bradycardia, hypotension, bronchoconstriction and a stress reaction consisting of flushing, headache, dyspnea, chest pressure and nausea. It is therefore unlikely, given the adverse effect profile of adenosine and adenosine analogues, that systemic administration of these agents could be used to treat or prevent gastrointestinal diseases or most systemic diseases. Accordingly, the aim of the present invention is to determine whether adenosine could be administered in such a way that the beneficial effects of adenosine therapy may be taken advantage of to treat or prevent gastrointestinal or systemic diseases without attendant adverse effects.
Accordingly, it is a primary object of the present invention to provide a method of peritoneal lavage with adenosine which provides therapeutically effective levels of adenosine in the intestines of a subject without substantially elevating adenosine levels in the systemic circulation of the subject.
Another object of the present invention is to provide a method of peritoneal lavage with an adenosine-releasing xe2x80x9cprodrugxe2x80x9d, i.e., a compound metabolized to adenosine, to provide pharmacological levels of adenosine in the intestines of a subject without elevating adenosine levels in the systemic circulation of the subject.
Still another object of the present invention is to provide a method of peritoneal lavage with adenosine -5xe2x80x2-monophosphate (xe2x80x9cAMPxe2x80x9d), an adenosine-releasing prodrug, to provide pharmacological levels of adenosine in the intestines of a subject without elevating adenosine levels in the systemic circulation of the subject.
Another object of the present invention is to provide a method of intraperitoneal administration of adenosine which confers therapeutic benefits, both locally and systemically, in a subject such as improved renal function, improved metabolic status, and improved survival in hemorrhagic shock.
These and other objects of the of the present invention are achieved by one or more of the following embodiments.
In one aspect, the invention features a method for preventing or treating gastrointestinal or systemic diseases in a mammalian subject, comprising:
the step of administering a therapeutically effective amount of a composition comprising adenosine or a prodrug thereof into the peritoneal cavity of the subject at a dose that does not achieve pharmacologically active levels in the aortic arterial plasma of the subject.
In preferred embodiments the phosphate ester of adenosine is selected from the group consisting of adenosine-5xe2x80x2-monophosphate, adenosine-5xe2x80x2-diphosphate, adenosine-5xe2x80x2-triphosphate, and adenosine 3xe2x80x2:5xe2x80x2-cyclic monophosphate.
In another aspect, the invention features a pharmaceutical composition for treating gastrointestinal or inflammatory diseases in a mammalian subject, wherein the composition comprises adenosine or a prodrug thereof and a pharmaceutically acceptable carrier, and wherein the composition is administered into the peritoneal cavity of the subject at a therapeutically effective dose that does not achieve pharmacologically active levels in the aortic arterial plasma of the subject.
In yet another preferred embodiment, the phosphate ester of adenosine is selected from the group consisting of adenosine-5xe2x80x2-monophosphate, adenosine-5xe2x80x2-diphosphate, adenosine-5xe2x80x2-triphosphate, and adenosine 3xe2x80x2:5xe2x80x2-cyclic monophosphate.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiment, and from the claims.